1. Field of the Invention
The present invention relates to suppressing the growth of cancer and other proliferative diseases by the administering of novel compounds that exhibit progesterone antagonism. The present invention also relates to processes of preparation and the use in therapy of such novel compounds.
2. Description of the Relevant Art
In the past, progesterone antagonists have been postulated to be of potential benefit in the treatment of breast cancer where the primary lesion contains both estrogen and progesterone receptors. In a recent study of an in vivo rat model of progesterone receptor positive breast cancer, it was shown that the administration of a new antiprogestin (PROELLEX, CDB-4124) resulted in a regression of tumor size as well as a decrease in the development of new tumors. FIG. 1 shows a series of selected progesterone antagonists that have been shown to be effective in vitro and in vivo. The prototype antagonist, Mifepristone (see FIG. 1), is characterized by the 19-nor-4,9-diene steroid nucleus, the 17α-propynyl-17β-hydroxy functionality, and the 11β-(4-dimethylamino)phenyl functional group which is believed to be responsible for its antagonistic activity. While Mifepristone is a potent progesterone antagonist, its long-term clinical use is limited due to its overt glucocorticoid receptor antagonism. Subsequent development undertaken by several groups has led to the discovery of several novel progesterone antagonists that are both more active than Mifepristone and more dissociated in relation to glucocorticoid antagonism. Some notable examples as outlined above in FIG. 1 and include Onapristone, ORG-33628, PROELLEX, and Lonaprisan (ZK-230211).
Of these examples, Lonaprisan is most notable in that it exhibits the highest antiprogestagenic activity and displays only marginal antiglucocorticoid effects. The high activity of Lonaprisan in comparison with the other analogs is somewhat surprising in that the normal effect on the introduction of a 17α-alkyl group in steroids is to increase its interaction with the androgen receptor, an effect not seen with this compound. However, the substitution of fluorine for hydrogen can often induce significant biochemical changes in a pharmaceutical molecule while causing only a slight change in its shape.
While antiprogestin therapies have been effective in the treatment of some forms of cancer (including breast cancers), there is still a need to develop more effective therapies.